See the below details regarding information on the original 2020 trials:
VERY IMPORTANT (Analysis of deaths in the cohorts of Pfizer trial) – Forensic Analysis of the 38 Subject Deaths in the 6-Month Interim Report of the Pfizer/BioNTech BNT162b2 mRNA Vaccine Clinical Trial https://www.preprints.org/manuscript/202309.0131/v1 Published https://ijvtpr.com/index.php/IJVTPR/article/view/86
Authors found:
The analysis reported here is unique in that it is the first study of the original data from the Pfizer/BioNTech BNT162b2 mRNA vaccine clinical trial (CA4591001) to be carried out by a group unaffiliated with the trial sponsor. Our study is a forensic analysis of the 38 trial subjects who died between July 27, 2020, the start of Phase 2/3 of the clinical trial, and March 13, 2021, the data end date of their 6-Month Interim Report. Phase 2/3 of the trial involved 44,060 subjects who were equally distributed into two groups and received Dose 1 of either the BNT162b2 mRNA vaccinated or the Placebo control (0.9% normal saline). At Week 20, when the BNT162b2 mRNA vaccine received Emergency Use Authorization from the U.S. FDA, subjects in the placebo arm were given the option to be BNT162b2 vaccinated. All but a few accepted. Surprisingly, a comparison of the number of subject deaths per week during the 33 Weeks of this study found no significant difference between the number of deaths in the vaccinated versus placebo arms for the first 20 weeks of the trial, the placebo-controlled portion of the trial. After Week 20, as subjects in the Placebo were unblinded and vaccinated, deaths among this still unvaccinated cohort of this group slowed and eventually plateaued. Deaths in the BNT162b2 vaccinated subjects continued at the same rate. Our analysis revealed inconsistencies between the subject data listed in the 6-Month Interim Report and publications authored by Pfizer/BioNTech trial site administrators. Most importantly, we found evidence of an over 3.7-fold increase in number of deaths due to cardiovascular events in BNT162b2 vaccinated subjects compared to Placebo controls. This significant adverse event signal was not reported by Pfizer/BioNTech. Potential sources of these data inconsistencies are identified.
IMPORTANT (BMJ Letter to Editor regarding different manufacturing processes for trial and rollout) – Effect of mRNA Vaccine Manufacturing Processes on Efficacy and Safety Still an Open Question https://www.bmj.com/content/378/bmj.o1731/rr-2
Authors note:
An October 2020 amendment to the protocol of the pivotal Pfizer/BioNTech BNT162b2 (Comirnaty) clinical trial (C4591001) indicates that nearly all vaccine doses used in the trial came from ‘clinical batches’ manufactured using what is referred to as ‘Process 1’.[3] However, in order to upscale production for large-scale distribution of ‘emergency supply’ after authorization, a new method was developed, ‘Process 2’. The differences include changes to the DNA template used to transcribe the RNA and the purification phase, as well as the manufacturing process of the lipid nanoparticles. Notably, ‘Process 2’ batches were shown to have substantially lower mRNA integrity.[4,5]
The protocol amendment states that “each lot of ‘Process 2’-manufactured BNT162b2 would be administered to approximately 250 participants 16 to 55 years of age” with comparative immunogenicity and safety analyses conducted with 250 randomly selected ‘Process 1’ batch recipients. To the best of our knowledge, there is no publicly available report on this comparison of ‘Process 1’ versus ‘Process 2’ doses.
Two documents obtained through a Freedom of Information Act (FOIA) request[6] describe the vaccine batches and lots supplied to each of the trial sites through November 19, 2020[7] and March 17, 2021,[8] respectively. According to these documents, doses from ‘Process 2’ batch EE8493Z are listed at four trial sites prior to November 19, and four other sites are listed with ‘Process 2’ batch EJ0553Z in the updated document. Both batches were also part of the emergency supply for public distribution. The CDC’s Vaccine Adverse Event Reporting System, known to be underreported,[9] lists 658 reports (169 serious, 2 deaths) for lot EE8493[10] and 491 reports (138 serious, 21 deaths) for lot EJ0553.[11]
Furthermore, additional ‘Process 1’ batch EE3813 doses with distinct Pfizer lot numbers were added to the later batch document[7] at over 70% of trial sites, potentially supplied at a later stage to enable vaccination of placebo patients with BNT162b2. The 6-month interim clinical study report[12] from the Comirnaty trial notes that “the IR for any AE and at least 1 related AE and severe AE for participants who originally received placebo and then received BNT162b2 are greater (205.4 per 100 PY, 189.5 per 100 PY, 6.0 per 100 PY) than the IRs (83.2 per 100 PY, 62.9 per 100 PY, 4.3 per 100 PY) for participants who originally were randomized to BNT162b2” (p222). It is unclear whether there is a connection between the lots administered to the crossover placebo subjects and the elevated rate of AE’s.
Finally, a recent study found significant variability in the rate of serious adverse events (SAEs) across 52 different lots of Comirnaty marketed in Denmark.[13] This finding underscores the importance of understanding better the potential impact of variability in the production process of COVID-19 mRNA vaccines on efficacy and safety.
Research Protocols
1. Pfizer – A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS https://cdn.pfizer.com/pfizercom/2020-11/C4591001_Clinical_Protocol_Nov2020.pdf (Link removed by Pfizer) Protocol https://media.tghn.org/medialibrary/2020/11/C4591001_Clinical_Protocol_Nov2020_Pfizer_BioNTech.pdf
ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04368728
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, and 65 and 85 years, inclusive (Phase 1), or ≥12 years (Phase 2/3), at randomization. Note that
participants <18 years of age cannot be enrolled in the EU.
• Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination (if required), and clinical judgment of the investigator to be eligible for inclusion in the study.
Note: Healthy participants with preexisting stable disease, defined as disease not
requiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participantswith known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) can be found in Section 10.8.
4. Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk for acquiring COVID-19 (including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers)
2. AstraZeneca – A Phase III Randomized, Double-blind, Placebo-controlled Multicenter Study in Adults to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector
Vaccine, for the Prevention of COVID-19 https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf
3. Moderna – A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older https://www.nejm.org/doi/suppl/10.1056/NEJMoa2035389/suppl_file/nejmoa2035389_protocol.pdf
COVID-19 vaccine efficacy and effectiveness—the elephant (not) in the room
https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00069-0/fulltext
Vaccine efficacy is generally reported as a relative risk reduction (RRR). It uses the relative risk (RR)—ie, the ratio of attack rates with and without a vaccine—which is expressed as 1–RR. Ranking by reported efficacy gives relative risk reductions of 95% for the Pfizer–BioNTech, 94% for the Moderna–NIH, 91% for the Gamaleya, 67% for the J&J, and 67% for the AstraZeneca–Oxford vaccines. However, RRR should be seen against the background risk of being infected and becoming ill with COVID-19, which varies between populations and over time. Although the RRR considers only participants who could benefit from the vaccine, the absolute risk reduction (ARR), which is the difference between attack rates with and without a vaccine, considers the whole population. ARRs tend to be ignored because they give a much less impressive effect size than RRRs: 1·3% for the AstraZeneca–Oxford, 1·2% for the Moderna–NIH, 1·2% for the J&J, 0·93% for the Gamaleya, and 0·84% for the Pfizer–BioNTech vaccines.
ARR is also used to derive an estimate of vaccine effectiveness, which is the number needed to vaccinate (NNV) to prevent one more case of COVID-19 as 1/ARR. NNVs bring a different perspective: 81 for the Moderna–NIH, 78 for the AstraZeneca–Oxford, 108 for the Gamaleya, 84 for the J&J, and 119 for the Pfizer–BioNTech vaccines. The explanation lies in the combination of vaccine efficacy and different background risks of COVID-19 across studies: 0·9% for the Pfizer–BioNTech, 1% for the Gamaleya, 1·4% for the Moderna–NIH, 1·8% for the J&J, and 1·9% for the AstraZeneca–Oxford vaccines.ARR (and NNV) are sensitive to background risk—the higher the risk, the higher the effectiveness—as exemplified by the analyses of the J&J’s vaccine on centrally confirmed cases compared with all cases:8 both the numerator and denominator change, RRR does not change (66–67%), but the one-third increase in attack rates in the unvaccinated group (from 1·8% to 2·4%) translates in a one-fourth decrease in NNV (from 84 to 64).There are many lessons to learn from the way studies are conducted and results are presented. With the use of only RRRs, and omitting ARRs, reporting bias is introduced, which affects the interpretation of vaccine efficacy.10 When communicating about vaccine efficacy, especially for public health decisions such as choosing the type of vaccines to purchase and deploy, having a full picture of what the data actually show is important, and ensuring comparisons are based on the combined evidence that puts vaccine trial results in context and not just looking at one summary measure, is also important. Such decisions should be properly informed by detailed understanding of study results, requiring access to full datasets and independent scrutiny and analyses.Unfortunately, comparing vaccines on the basis of currently available trial (interim) data is made even more difficult by disparate study protocols, including primary endpoints (such as what is considered a COVID-19 case, and when is this assessed), types of placebo, study populations, background risks of COVID-19 during the study, duration of exposure, and different definitions of populations for analyses both within and between studies, as well as definitions of endpoints and statistical methods for efficacy. Importantly, we are left with the unanswered question as to whether a vaccine with a given efficacy in the study population will have the same efficacy in another population with different levels of background risk of COVID-19. This is not a trivial question because transmission intensity varies between countries, affected by factors such as public health interventions and virus variants. The only reported indication of vaccine effectiveness is the Israeli mass vaccination campaign using the Pfizer–BioNTech product. Although the design and methodology are radically different from the randomised trial,2 Dagan and colleagues11 report an RRR of 94%, which is essentially the same as the RRR of the phase 3 trial (95%) but with an ARR of 0·46%, which translates into an NNV of 217 (when the ARR was 0·84% and the NNV was 119 in the phase 3 trial). This means in a real-life setting, 1·8 times more subjects might need to be vaccinated to prevent one more case of COVID-19 than predicted in the corresponding clinical trial.Uncoordinated phase 3 trials do not satisfy public health requirements; platform trials designed to address public health relevant questions with a common protocol will allow decisions to be made, informed by common criteria and uniform assessment. These considerations on efficacy and effectiveness are based on studies measuring prevention of mild to moderate COVID-19 infection; they were not designed to conclude on prevention of hospitalisation, severe disease, or death, or on prevention of infection and transmission potential. Assessing the suitability of vaccines must consider all indicators, and involve safety, deployability, availability, and costs.
Outcome Reporting Bias in COVID-19 mRNA Vaccine Clinical Trials
https://www.mdpi.com/1648-9144/57/3/199
Relative risk reduction and absolute risk reduction measures in the evaluation of clinical trial data are poorly understood by health professionals and the public. The absence of reported absolute risk reduction in COVID-19 vaccine clinical trials can lead to outcome reporting bias that affects the interpretation of vaccine efficacy. The present article uses clinical epidemiologic tools to critically appraise reports of efficacy in Pfzier/BioNTech and Moderna COVID-19 mRNA vaccine clinical trials. Based on data reported by the manufacturer for Pfzier/BioNTech vaccine BNT162b2, this critical appraisal shows: relative risk reduction, 95.1%; 95% CI, 90.0% to 97.6%; p = 0.016; absolute risk reduction, 0.7%; 95% CI, 0.59% to 0.83%; p < 0.000. For the Moderna vaccine mRNA-1273, the appraisal shows: relative risk reduction, 94.1%; 95% CI, 89.1% to 96.8%; p = 0.004; absolute risk reduction, 1.1%; 95% CI, 0.97% to 1.32%; p < 0.000. Unreported absolute risk reduction measures of 0.7% and 1.1% for the Pfzier/BioNTech and Moderna vaccines, respectively, are very much lower than the reported relative risk reduction measures. Reporting absolute risk reduction measures is essential to prevent outcome reporting bias in evaluation of COVID-19 vaccine efficacy – Read the full article.
IMPORTANT (RRR detail) – Understanding Relative Risk Reduction (RRR) and Absolute Risk Reduction (ARR) in Vaccine Trials https://pandata.org/understanding-relative-risk-reduction-and-absolute-risk-reduction-in-vaccine-trials/
The vaccine appeared to reduce the relative risk of COVID-19 (as defined by Pfizer) by an estimated 95% over the short duration of the trial, but the interpretation of that number is not that simple. It’s nearly impossible to extrapolate the potential real world benefit from such a limited trial design.
Firstly we must understand the role of statistics here. If you toss a coin 10 times you would expect to get 50% heads and 50% tails on average. In practice, however, it would not be too surprising to obtain 7 heads and 3 tails in any 10 tosses of the coin. There are similar considerations that apply to any medical trial. Although the headline figure here is a 95% relative risk reduction, how confident are we that this figure is close to the truth? If we had run the trial at another time, might we have only recorded a value of 90% for the RRR? So any quoted reduction must also come with some indication of how “good” that number is. While the Pfizer trail had 40000+ participants, relatively few were infected with COVID, leaving the conclusions to be based on small numbers.
In order to determine if the administration of the vaccine to the population is really beneficial, we also need to consider the actual risk of disease in those who did not receive the intervention. To illustrate with an exaggerated example, if the risk of acquiring a disease is only one in a million, reducing it by half, to one in 2 million is not a big deal. If, however, the risk of acquiring a disease is 30%, reducing the risk to 15% is very significant. If our proposed experimental treatment caused side effect deaths at a rate of one in a million we would be hesitant to recommend it in the above example, but we would be much more likely to recommend it for the latter.
The Pfizer study includes a figure that compares the cumulative number of vaccinated patients that became ill versus the cumulative number of placebo patients that became ill. The graph looks similar to this:
This appears to be an impressive result, as there are more cases in the placebo group RELATIVE to the vaccinated group. But note the Y axis only goes to 2.5% – so that in total 2.3% of placebo patients became ill versus .3% of vaccinated patients. If we look at the
ABSOLUTE RISK of each group, the results look far less impressive:
Is the benefit worth the cost?
This is the same question we asked in the rubberized lightning suit example above. It is the more difficult subjective question of whether our proposed measure is worth it. In the case of a serious disease like Covid19 this is a complex question because whilst we want to save lives, we also recognize that the vaccines, like all medical interventions, are not free from serious side effects. Even though only a small percentage suffer such effects, we must weigh this against the fact that we are also dealing with mostly small percentages of people (depending on personal risk factors) who die from COVID-19. The ARR and RRR are both important parameters that help us in addressing these complex issues
This illustrates why considering the ARR may be helpful. In the Pfizer clinical trial mentioned above, the risk of COVID-19 = 0.75%; so, reducing this risk by 95% does not seem like a very impressive effect. But the issue becomes even more complex to interpret. Within the clinical trial, different subgroups of people have different risks of getting COVID-19. Furthermore, different age groups have vastly differing risks of mortality from COVID-19. We cannot simply assume that a relative risk reduction of 95% applies uniformly across all age ranges from the trial data without further age stratification of the results. In general, younger people have massively lower risks from COVID-19, so the ARR is tiny in those groups. In addition, the risk of getting the disease in different sectors of the population, and in different geographical locations, may also be different.
There is a final important point to consider relative to trial design and reported outcomes. Whilst it is important to determine whether the vaccines are effective at reducing infection, it is equally important to know whether they improve health outcomes overall – is the benefit sufficient to justify the potential risk? For example, in the vaccine trial discussed above, there were 262 serious adverse events noted in the vaccinated group and 172 serious adverse events noted in the placebo group (which admittedly seems odd as one wouldn’t expect a saline injection to produce any adverse events). Given that, for the vast majority, COVID-19 is not a serious illness , adverse events arising during the trials should also factor into our decision about overall suitability of the proposed measure.
The logical conclusion is that the RRR and ARR of an intervention (in this case a vaccine) reported in a RCT should be interpreted carefully when making decisions about the desirability of implementing the intervention in the general population. It is not sound public health practice to say: “This vaccine is 95% effective, so let’s give it to everyone”. The decisions to implement interventions in the population should use results of a RCT as valuable information, but should also take into account many factors such as the actual risk of getting COVID-19 in different populations (geographical locations, different ages, other medical conditions…), the probability of getting sick with COVID-19 during different seasons, and the probability of adverse events following vaccination among others.
IMPORTANT (In depth paper on the original trials and NNV plus harms – fully referenced) – COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign
https://www.cureus.com/articles/203052#!/
IMPORTANT – Covid-19: Researcher blows the whistle on data integrity issues in Pfizer’s vaccine trial
https://pubmed.ncbi.nlm.nih.gov/34728500/
IMPORTANT – KOSTOV – Why are we vaccinating children against COVID-19?
https://www.sciencedirect.com/science/article/pii/S221475002100161X#bib0030
Highlights
- Bulk of COVID-19 per capita deaths occur in elderly with high comorbidities.
- Per capita COVID-19 deaths are negligible in children.
- Clinical trials for these inoculations were very short-term.
- Clinical trials did not address long-term effects most relevant to children.
- High post-inoculation deaths reported in VAERS (very short-term).
This article examines issues related to COVID-19 inoculations for children. The bulk of the official COVID-19-attributed deaths per capita occur in the elderly with high comorbidities, and the COVID-19 attributed deaths per capita are negligible in children. The bulk of the normalized post-inoculation deaths also occur in the elderly with high comorbidities, while the normalized post-inoculation deaths are small, but not negligible, in children. Clinical trials for these inoculations were very short-term (a few months), had samples not representative of the total population, and for adolescents/children, had poor predictive power because of their small size. Further, the clinical trials did not address changes in biomarkers that could serve as early warning indicators of elevated predisposition to serious diseases. Most importantly, the clinical trials did not address long-term effects that, if serious, would be borne by children/adolescents for potentially decades.
A novel best-case scenario cost-benefit analysis showed very conservatively that there are five times the number of deaths attributable to each inoculation vs those attributable to COVID-19 in the most vulnerable 65+ demographic. The risk of death from COVID-19 decreases drastically as age decreases, and the longer-term effects of the inoculations on lower age groups will increase their risk-benefit ratio, perhaps substantially.
IMPORTANT (Original Phase 3 trial data reanalysed – Dr Syed) – Don’t be ARRsey https://arkmedic.substack.com/p/dont-be-arrsey?publication_id=413756&isFreemail=true
IMPORTANT – Dose of approved COVID-19 vaccines is based on weak evidence: a review of early-phase, dose-finding trials https://www.medrxiv.org/content/10.1101/2022.09.20.22276701v1
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